HIV-1-associated dementia (HAD) is an evolving neurological disorder. Previously an acute fulminate pathology, in the era of highly active antiretroviral therapy (HAART), it has become a chronic more insidious disorder. Individuals infected with HIV-1 continue to develop neurocognitive dysfunction but at lower rates, even though HIV-1-associated encephalitis is a persistent postmortem finding. We hypothesize that there will be a number of factors that taken together will profile individuals with HIV-1 at risk for dementia. We identify the potential risk factors for HAD as a high viral load, an APOE4 genotype, an inflammatory monocyte/macrophage phenotype, age, an increase in the chemokine MCP-1, polymorphisms in the TNFalpha and CCR5 genes, diabetes, a decrease in the neuronal marker NAA and increases in choline-containing metabolites and myo-inositol by MRS. We have compared gene expression microarrays on HIV-1-infected subjects with high and low viral loads and found that several genes are associated with high viral load that also correspond with several risk factors mentioned above. Our specific aims are: 1) To further develop the state of monocyte activation/dysfunction in HIV-1-infected individuals using gene microarrays, RT-PCR and Western analyses and link this to known risk factors; 2) to further characterize the role of specific differentially expressed genes or pathways from individuals with HIV-1 infection; 3) To determine the effect of HIV-1 infected monocyte/macrophage supernatants on human brain aggregates as surrogates for in vivo measures of brain structure and metabolites; and 4) to identify a monocyte gene expression profile from HIV-1-infected subjects that correlates with injury to specific brain structures and metabolites measured by MRI and MRSI, respectively, to correlate these with other risk factors. These findings will help us develop a monocyte profile for HIV-1-infected individuals at risk for dementia to receive preventive therapy as well as serve as markers to assess effective therapies. [unreadable] [unreadable]